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Blood, 23 April 2009, Vol. 113, No. 17, pp. 4027-4037. Prepublished online as a Blood First Edition Paper on December 18, 2008; DOI 10.1182/blood-2008-09-179796. This Article Full Text (PDF) Supplemental Methods and Figures All Versions of this Article: blood-2008-09-179796v1 113/17/4027    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Tiedemann, R. E Articles by Stewart, A K. Search for Related Content PubMed PubMed Citation Articles by Tiedemann, R. E Articles by Stewart, A K. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted September 17, 2008 Accepted December 1, 2008 Identification of a potent natural triterpenoid inhibitor of proteosome chymotrypsin-like activity and NF-B with anti-myeloma activity in vitro and in vivo Rodger E Tiedemann*, Jessica Schmidt, Jonathan J. Keats, Chang-Xin Shi, Yuan Xiao Zhu, Stephen E. Palmer, Xinliang Mao, Aaron D Schimmer, and A Keith Stewart Comprehensive Cancer Center, Mayo Clinic, Scottsdale, AZ, United States Ontario Cancer Institute, Princess Margaret Hospital, Toronto, ON, Canada The Sinai-McLaughlin Assay and Robotic Technologies Facility, Mount Sinai Hospital, Toronto, ON, Canada * Corresponding author; email: tiedemann.rodger{at}mayo.edu. As multiple myeloma tumors universally dysregulate cyclin D genes we conducted high-throughput chemical library screens for compounds that induce suppression of cyclin D2 promoter transcription. The top-ranked compound was a natural triterpenoid, pristimerin. Strikingly, the early transcriptional response of cells treated with pristimerin closely resembles cellular responses elicited by proteosome inhibitors, with rapid induction of heat shock proteins, activating transcription factor (ATF) 3 and CHOP. Enzymatic assays and immunoblotting confirm that pristimerin rapidly (<90min) and specifically inhibits chymotrypsin-like proteosome activity at low concentrations (<100nM) and causes accumulation of cellular ubiquitinated proteins. Notably, cytotoxic triterpenoids including pristimerin inhibit NF-B activation via inhibition of IKK or IKK, while proteosome inhibitors also suppress NF-B function by impairing degradation of ubiquitinated-IB. By inhibiting both IKK and the proteosome pristimerin causes overt suppression of constitutive NF-B activity in myeloma cells that may mediate its suppression of cyclin D. Multiple myeloma is exquisitely sensitive to proteosome or NF-B pathway inhibition. Consistent with this, pristimerin is potently and selectively lethal to primary myeloma cells (IC50<100nM), inhibits xenografted plasmacytoma tumors in mice and is synergistically cytotoxic with bortezomib - providing the rationale for pharmaceutical development of triterpenoid dual-function proteosome/NF-B inhibitors as therapeutics for human multiple myeloma and related malignancies. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J.-Y. Byun, M.-J. Kim, D.-Y. Eum, C.-H. Yoon, W.-D. Seo, K. H. Park, J.-W. Hyun, Y.-S. Lee, J.-S. Lee, M.-Y. Yoon, et al. Reactive Oxygen Species-Dependent Activation of Bax and Poly(ADP-ribose) Polymerase-1 Is Required for Mitochondrial Cell Death Induced by Triterpenoid Pristimerin in Human Cervical Cancer Cells Mol. Pharmacol., October 1, 2009; 76(4): 734 - 744. [Abstract] [Full Text] [PDF]

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